Cells in many tissues display polarity within the plane of the tissue. This is often called planar cell polarity (PCP) and this project focuses on the genetic, cell biological and molecular basis for PCP. Previous work funded by this grant discovered a genetic regulatory pathway for PCP in the Drosophila model system and it has been found to be conserved in vertebrates including humans. Mutations in PCP genes have been linked to a failure in neural closure, polycystic kidney disease, hearing and balance problems and heart and lung developmental defects. The pathway consists of a regulatory hierarchy, with the fz-like PCP genes being upstream of the planar polarity effector (PPE) genes which are in turn upstream of the mwh gene. The proteins that are encoded by pathway genes all accumulate asymmetrically in epithelial cells and this is thought to be essential to their function. A major goal of the application is to understand how polarity information is passed on from one group to the next in the hierarchy. A variety of genetic and biochemical experiments are designed to test models about how this is accomplished. The second aim of the proposal is to determine the stoichiometry of proteins in the PCP complexes. An innovative microscopy approach will be taken. The final aim is to determine where in the PCP hierarchy a number of newly identified PCP genes function. PUBLIC HEALTH RELEVANCE: The conserved PCP regulatory pathway is essential for the proper morphogenesis of a wide variety of cells, tissues and organs including the epidermis, stereocilia of the inner ear, muscle, bone, heart, lung, kidney and embryonic tissues undergoing cellular movements. Mutations of genes in this pathway have been found to be associated with a failure of neural tube closure, polycystic kidney disease, cancer and hearing and balance problems. This project is focused on understanding the function of several genes in this pathway, which could lead to potential treatments for these health problems.